Effectiveness of lapatinib treatment on bleomycin induced experimental scleroderma model

Scleroderma is a connective tissue disease characterized by endothelial damage and diffuse interstitial fibrosis. Pulmonary fibrosis occuring during the course of disease isone of the most important causes of morbidity and mortality. Although the pathogenesis of scleroderma is not exactly known, it is thought that vasculopathy and immune activation take important roles in pathogenesis. Lapatinib, a tyrosine kinase inhibitor, is a derivative of 4-anilinoquinol. It reversibly binds intracellular-tyrosine kinase regions of EGFR1 and 2, and inhibits substrate phosphorylation. Thus, it stops the flow of many important pathways such as MAPK and PI3K. Consequently, it affects cell cycle progression, apoptosis, angiogenesis and cell adhesion. The purpose of our study is to determine the prophylactic and therapeutic efficacy of lapatinib on bleomycin (BLM) induced experimental model of scleroderma. 60 Balb/c female mice with average of 6 weeks of age and 20-25 grams in weight were included in this study and they were divided into 6 equal groups as 10 in each group. To the control mice (group A and group D), sc daily saline buffered with phosphate (PBS) was administered. BLM dissolving in FTS was administered daily for 3 weeks to the rats in groups B and C and for 6 weeks to mice in groups E and F sc at a dose 100 mcL (100 mcg). In addition to the BLM, rats in Group C (prophylactic lapatinib) starting from the first day of the study and group F (therapeutic lapatinib) from day 21, received sc lapatinib at a dose of 30 mg/ kg until the end of study. Mice in group A, B and C were sacrified on third week and those in group D,E and F on sixth week and tissue samples were removed for analyzes. Tissue TGF-β1 and fibronectin-1 mRNA expressions were determined by RT-PCR method. Repeated subcutaneous administration of BLM caused, in early and late stages, dermal inflammatory cell infiltration, increase in dermal thickness dermal fibrosis. Similarly; TGF-β1 and fibronectin-1 mRNA expressions were evidently increased. In both prophylactic and therapeutic applications of lapatinib, TGF-β1 and fibronectin-1 mRNA expressions decreased markedly. In addition, histopathologically dermal necro- inflammation and fibrosis wer detected to be decreased. Lapatinib may exhibit anti-fibrotic effects in BLM-induced dermal fibrosis model. Studies show that lapatinib is a potential therapeutic agent but it needs to be confirmed with in vivo studies. Keywords: Experimental scleroderma, tyrosine kinase, lapatinib.